Pathology and diagnostic criteria of gastrointestinal stromal tumors (GISTs): a review.

Gastrointestinal stromal tumor (GIST) is the designation for the specific c-kit expressing and Kit-signaling driven mesenchymal tumors, many of which have Kit-activating mutations. The specific identification of GIST has become increasingly important because a Kit-selective tyrosine kinase inhibitor, imatinib (Glivec, formerly known as STI571, Novartis Pharma AG, Basel, Switzerland), has shown promise as an effective adjuvant therapy treatment. GISTs are the most common mesenchymal tumors of the gastrointestinal (GI) tract. We estimate the frequency of malignant GISTs as 20% to 30% of the frequency of all soft-tissue sarcomas, but small benign tumors, often found incidentally during unrelated surgery or autopsy, are probably much more common. Older adults are most at risk for GIST; very rarely, GIST occurs in children and young adults (sometimes connected with Carney's triad), or on a familial basis. GISTs have been documented in all parts of the GI tract. A great majority of them occur in the stomach (60% to 70%) and small intestine (25% to 35%), with rare occurrence in the colon and rectum (5%), esophagus (<2%) and appendix. Some GISTs are primary in the omentum, mesentery or retroperitoneum, and are unrelated to the tubular GI tract. GISTs can be histologically identified as highly cellular spindle cell or epithelioid mesenchymal tumors, and morphology is somewhat site-dependent. However, common to all these tumors is expression of Kit (CD117 antigen), which is a major diagnostic criterion. Few other Kit-positive mesenchymal tumors of the GI tract are likely to be confused with GISTs; exceptions are metastatic melanoma and related tumors and malignant vascular tumors. Additional diagnostic criteria include common positivity for CD34 (70%), variable expression of smooth muscle actins (20% to 30%) and S100 protein (10%) and almost uniform negativity for desmin (only 2% to 4% of GISTs are positive). Although the prediction of malignancy in this tumor group is notoriously difficult, tumors that have mitotic activity counts exceeding 5 per 50 high power fields (HPF) or those larger than 5 cm have a high frequency of intra-abdominal recurrence and liver metastasis. In contrast, tumors smaller than 2 cm and those with mitotic activity counts <5 per 50 HPF are likely to be benign. These diagnostic criteria leave an inevitable gray area in the separation of benign and malignant tumors. Kit-activating mutations can be detected in at least 60% to 70% of GIST cases. Most of the mutations, in-frame deletions of several codons, are located in the juxtamembrane domain (exon 11) of the gene. Less commonly, mutations have been detected in the extracellular domain (exon 9), and tyrosine kinase domains (exons 13 and 17). Functional analysis of the different c-kit mutations and their impact on the response to tyrosine kinase inhibitors are under intense investigation.